Single-cell multi-cohort dissection of the schizophrenia transcriptome

• 成果类型: Article
• 署名作者: Ruzicka, W. Brad; Mohammadi, Shahin; Fullard, John F.; Davila-Velderrain, Jose; Subburaju, Sivan; Tso, Daniel Reed; Hourihan, Makayla; Jiang, Shan; Lee, Hao-Chih; Bendl, Jaroslav; Voloudakis, Georgios; Haroutunian, Vahram; Hoffman, Gabriel E.; Roussos, Panos; Kellis, Manolis
• 署名单位: Harvard University; Harvard University Medical Affiliates; McLean Hospital; Harvard University; Harvard Medical School; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Massachusetts Institute of Technology (MIT); Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Human Technopole; US Department of Veterans Affairs; Veterans Health Administration (VHA); James J. Peters VA Medical Center
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-10594
• DOI: 10.1126/science.adg5136
• 发表日期: 2024-05-24
• 关键词: prefrontal cortex; gene-expression; synaptic plasticity; gabaergic neurons; polygenic risk; neurodevelopment; hippocampus; deficits; IMPACT; loci

摘要

The complexity and heterogeneity of schizophrenia have hindered mechanistic elucidation and the development of more effective therapies. Here, we performed single-cell dissection of schizophrenia-associated transcriptomic changes in the human prefrontal cortex across 140 individuals in two independent cohorts. Excitatory neurons were the most affected cell group, with transcriptional changes converging on neurodevelopment and synapse-related molecular pathways. Transcriptional alterations included known genetic risk factors, suggesting convergence of rare and common genomic variants on neuronal population-specific alterations in schizophrenia. Based on the magnitude of schizophrenia-associated transcriptional change, we identified two populations of individuals with schizophrenia marked by expression of specific excitatory and inhibitory neuronal cell states. This single-cell atlas links transcriptomic changes to etiological genetic risk factors, contextualizing established knowledge within the human cortical cytoarchitecture and facilitating mechanistic understanding of schizophrenia pathophysiology and heterogeneity.